tbuckley/cabot-search huggingface dataset:
Phase II study of durvalumab (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC)
Authors: Benny Johnson, Cara L Haymaker, Edwin R Parra, Luisa Maren Solis Soto, Xuemei Wang, Jane V Thomas, Arvind Dasari, Van K Morris, Kanwal Raghav, Eduardo Vilar, Bryan K Kee, Cathy Eng, Christine M Parseghian, Robert A Wolff, Younghee Lee, Daniele Lorenzini, Caddie Laberiano-Fernandez, Anuj Verma, Wenhua Lang, Ignacio I Wistuba, Andrew Futreal, Scott Kopetz, Michael J Overman
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Monotherapy with immune checkpoint blockade is ineffective for patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC). This study investigates whether the combination of trametinib (T) with durvalumab (D) can alter the immune tumor microenvironment (TME) by successfully priming and activating T-cells. Methods Open-label, single-center, phase II trial with primary endpoint of immune-related response rate for combination of T+D in refractory MSS mCRC pts ( NCT03428126 ). T is 2 mg/day orally starting 1 week prior to D, which is given 1500 mg intravenously every 4 weeks. Simon 2-stage design used to enroll 29 pts into first stage, requiring a response in two or more pts to proceed to stage 2. Tumor biopsies were collected at baseline (BL) and early on-treatment (OT) at week 4. Results Twenty nine treated pts include 48% females, median age 48 years (range 28–75), and median prior therapies 2 (range 1–5). No grade (G) 4 or 5 treatment-related adverse events (TRAE). The most common TRAE of any grade was acneiform rash, 17% being G3. One of 29 pts had confirmed partial response (PR) lasting 9.3 months (mo) for an overall response rate of 3.4%. Seven pts had stable disease (SD) and five pts (1 PR, 4 SD) demonstrated decrease in total carcinoembryonic antigen ng/mL (best percentage reduction: 94%, 95%, 42%, 34%, and 22%, respectively). Median progression-free survival was 3.2 mo (range 1.1–9.3 months). Three pts with both liver and lung metastases demonstrated discrepant responses in which clinical benefit was present in the lung metastases but not liver metastases. Comparison of BL and 4-week OT tumor tissue flow cytometry demonstrated no changes in T-cell infiltration but upregulation expression of PD-1 and Tim3 on CD8 T cells. However, expression of PD-1 and Tim3 as single markers and as coexpressed markers was observed to increase OT relative to BL (p=0.03, p=0.06 and p=0.06, respectively). Conclusions T+D demonstrated acceptable tolerability in pts with refractory MSS mCRC. The response rate in the first stage of the study did not meet efficacy criteria to proceed to the second stage. Specific site of metastatic disease may impact outcomes in novel immunotherapy combination trials. Trial registration number NCT03428126 .
Human gut microbiota after bariatric surgery alters intestinal morphology and glucose absorption in mice independently of obesity
Authors: Fernando F Anhê, Soumaya Zlitni, Song-Yang Zhang, Béatrice So-Yun Choi, Cassandra Y Chen, Kevin P Foley, Nicole G Barra, Michael G Surette, Laurent Biertho, Denis Richard, André Tchernof, Tony K T Lam, Andre Marette, Jonathan Schertzer
Journal: Gut (2022)

Objective Bariatric surgery is an effective treatment for type 2 diabetes (T2D) that changes gut microbial composition. We determined whether the gut microbiota in humans after restrictive or malabsorptive bariatric surgery was sufficient to lower blood glucose. Design Women with obesity and T2D had biliopancreatic diversion with duodenal switch (BPD-DS) or laparoscopic sleeve gastrectomy (LSG). Faecal samples from the same patient before and after each surgery were used to colonise rodents, and determinants of blood glucose control were assessed. Results Glucose tolerance was improved in germ-free mice orally colonised for 7 weeks with human microbiota after either BPD-DS or LSG, whereas food intake, fat mass, insulin resistance, secretion and clearance were unchanged. Mice colonised with microbiota post-BPD-DS had lower villus height/width and crypt depth in the distal jejunum and lower intestinal glucose absorption. Inhibition of sodium-glucose cotransporter (Sglt)1 abrogated microbiota-transmissible improvements in blood glucose control in mice. In specific pathogen-free (SPF) rats, intrajejunal colonisation for 4 weeks with microbiota post-BPD-DS was sufficient to improve blood glucose control, which was negated after intrajejunal Sglt-1 inhibition. Higher Parabacteroides and lower Blautia coincided with improvements in blood glucose control after colonisation with human bacteria post-BPD-DS and LSG. Conclusion Exposure of rodents to human gut microbiota after restrictive or malabsorptive bariatric surgery improves glycaemic control. The gut microbiota after bariatric surgery is a standalone factor that alters upper gut intestinal morphology and lowers Sglt1-mediated intestinal glucose absorption, which improves blood glucose control independently from changes in obesity, insulin or insulin resistance.
Diagnostic evaluation of the sacroiliac joints for axial spondyloarthritis: should MRI replace radiography?
Authors: Denis Poddubnyy, Torsten Diekhoff, Xenofon Baraliakos, Kay Geert A Hermann, Joachim Sieper
Journal: Annals of the Rheumatic Diseases (2022)

The possibility of detection of structural damage on magnetic resonance imaging (MRI) of sacroiliac joints raises the question of whether MRI can substitute radiographs for diagnostic evaluation and to a further extent for classification of axial spondyloarthritis (axSpA). In this viewpoint, we will argue that it is time to replace conventional radiographs with MRI for the assessment of structural changes in sacroiliac joints. This message is based on current data on the following questions: (1) How reliable are conventional radiographs in the diagnosis of axSpA overall and radiographic axSpA in particular? (2) How does T1-weighted MRI compare to radiographs in the detection of sacroiliitis? (3) Are there now other (better) MRI sequences than T1-weighted, which might be more suitable for the detection of structural lesions? (4) Which MRI sequences should be performed for the diagnostic evaluation of the sacroiliac joints? (5) Do we have data to define sacroiliitis based on structural changes detected by MRI?
Coexisting autoantibodies against transcription factor Sp4 are associated with decreased cancer risk in patients with dermatomyositis with anti-TIF1γ autoantibodies
Authors: Yuji Hosono, Brandon Sie, Iago Pinal-Fernandez, Katherine Pak, Christopher A Mecoli, Maria Casal-Dominguez, Blake M Warner, Mariana J Kaplan, Jemima Albayda, Sonye Danoff, Thomas E Lloyd, Julie J Paik, Eleni Tiniakou, Rohit Aggarwal, Chester V Oddis, Siamak Moghadam-Kia, Carmelo Carmona-Rivera, Jose César Milisenda, Josep Maria Grau-Junyent, Albert Selva-O'Callaghan, Lisa Christopher-Stine, H Benjamin Larman, Andrew Lee Mammen
Journal: Annals of the Rheumatic Diseases (2022)

In dermatomyositis (DM), autoantibodies are associated with unique clinical phenotypes. For example, anti-TIF1γ autoantibodies are associated with an increased risk of cancer. The purpose of this study was to discover novel DM autoantibodies.
Distinct blood protein profiles associated with the risk of short-term and mid/long-term clinical relapse in patients with Crohn’s disease stopping infliximab: when the remission state hides different types of residual disease activity
Authors: Nicolas Pierre, Vân Anh Huynh-Thu, Thomas Marichal, Matthieu Allez, Yoram Bouhnik, David Laharie, Arnaud Bourreille, Jean-Frédéric Colombel, Marie-Alice Meuwis, Edouard Louis
Journal: Gut (2022)

Objective Despite being in sustained and stable remission, patients with Crohn’s disease (CD) stopping anti-tumour necrosis factor α (TNFα) show a high rate of relapse (~50% within 2 years). Characterising non-invasively the biological profiles of those patients is needed to better guide the decision of anti-TNFα withdrawal. Design Ninety-two immune-related proteins were measured by proximity extension assay in serum of patients with CD (n=102) in sustained steroid-free remission and stopping anti-TNFα (infliximab). As previously shown, a stratification based on time to clinical relapse was used to characterise the distinct biological profiles of relapsers (short-term relapsers: &lt;6 months vs mid/long-term relapsers: &gt;6 months). Associations between protein levels and time to clinical relapse were determined by univariable Cox model. Results The risk (HR) of mid/long-term clinical relapse was specifically associated with a high serum level of proteins mainly expressed in lymphocytes (LAG3, SH2B3, SIT1; HR: 2.2–4.5; p&lt;0.05), a low serum level of anti-inflammatory effectors (IL-10, HSD11B1; HR: 0.2–0.3; p&lt;0.05) and cellular junction proteins (CDSN, CNTNAP2, CXADR, ITGA11; HR: 0.4; p&lt;0.05). The risk of short-term clinical relapse was specifically associated with a high serum level of pro-inflammatory effectors (IL-6, IL12RB1; HR: 3.5–3.6; p&lt;0.05) and a low or high serum level of proteins mainly expressed in antigen presenting cells (CLEC4A, CLEC4C, CLEC7A, LAMP3; HR: 0.4–4.1; p&lt;0.05). Conclusion We identified distinct blood protein profiles associated with the risk of short-term and mid/long-term clinical relapse in patients with CD stopping infliximab. These findings constitute an advance for the development of non-invasive biomarkers guiding the decision of anti-TNFα withdrawal.
Remission and low disease activity (LDA) prevent damage accrual in patients with systemic lupus erythematosus: results from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort
Authors: Manuel Francisco Ugarte-Gil, John Hanly, Murray Urowitz, Caroline Gordon, Sang-Cheol Bae, Juanita Romero-Diaz, Jorge Sanchez-Guerrero, Sasha Bernatsky, Ann Elaine Clarke, Daniel J Wallace, David Alan Isenberg, Anisur Rahman, Joan T Merrill, Paul R Fortin, Dafna D Gladman, Ian N Bruce, Michelle Petri, Ellen M Ginzler, Mary Anne Dooley, Rosalind Ramsey-Goldman, Susan Manzi, Andreas Jönsen, Ronald F van Vollenhoven, Cynthia Aranow, Meggan Mackay, Guillermo Ruiz-Irastorza, Sam Lim, Murat Inanc, Ken Kalunian, Søren Jacobsen, Christine Peschken, Diane L Kamen, Anca Askanase, Bernardo A Pons-Estel, Graciela S Alarcón
Journal: Annals of the Rheumatic Diseases (2022)

To determine the independent impact of different definitions of remission and low disease activity (LDA) on damage accrual.
Publisher Correction: Limited proteolysis–mass spectrometry reveals aging-associated changes in cerebrospinal fluid protein abundances and structures
Authors: Steven R. Shuken, Jarod Rutledge, Tal Iram, Patricia Moran Losada, Edward N. Wilson, Katrin I. Andreasson, Ryan D. Leib, Tony Wyss-Coray
Journal: Nature Aging (2022)
Mind your language to catalyse the patient revolution
Authors: Kamran Abbasi
Journal: BMJ (2022)

Covid-wrongly-stalled the patient revolution.The voices of patients and citizens were lost amid responses to the pandemic that were too self-absorbed to consider the views of the people it affected the most.In one damning example, participants in unethical studies of ivermectin were exposed to its side effects without knowing that they were given the drug (doi:10.1136/bmj.o917). 1 Covid was also a free pass to tighten, loosen, or avoid public health measures, with little consultation or input from the public.The wisdom of hastily assembled, and generally unrepresentative, advisory committees and advisers was never more important and the exact opposite of the patient centred logic of "nothing about us, without us."11
The Impact of Obesity on Left Ventricular Mass and Geometry
Authors: Michael S. Lauer
Journal: JAMA (1991)

<h3>Objective.</h3> —To determine the relationship of varying degrees of obesity with left ventricular mass and geometry. <h3>Design.</h3> —Survey. <h3>Setting.</h3> —Population-based epidemiologic study. <h3>Participants and Methods.</h3> —M-mode echocardiograms, which were adequate for estimation of left ventricular mass, were obtained in 3922 healthy participants of the Framingham Heart Study. Measured height and weight were used to calculate body-mass index, a measure of obesity. <h3>Results.</h3> —Body-mass index was strongly correlated with left ventricular mass. After adjusting for age and blood pressure, body-mass index remained a strong independent predictor of left ventricular mass, left ventricular wall thickness, and left ventricular internal dimension (<i>P</i>&lt;.01 for all). Body-mass index was associated with prevalence of echocardiographic left ventricular hypertrophy, particularly in subjects with a body-mass index exceeding 30 kg/m<sup>2</sup>. <h3>Conclusions.</h3> —Obesity is significantly correlated with left ventricular mass, even after controlling for age and blood pressure. The increase in left ventricular mass associated with increasing adiposity reflects increases in both left ventricular wall thickness and left ventricular internal dimension. (<i>JAMA</i>. 1991;266:231-236)
Multimodal imaging demonstrates enhanced tumor exposure of PEGylated FUD peptide in breast cancer
Authors: Hye Jin Lee, Metti K. Gari, David R. Inman, Zachary T. Rosenkrans, Brian M. Burkel, Aeli P. Olson, Jonathan W. Engle, Reinier Hernandez, Suzanne M. Ponik, Glen S. Kwon
Journal: Journal of Controlled Release (2022)
Dll1-Mediated Notch Signaling Drives Tumor Cell Cross-talk with Cancer-Associated Fibroblasts to Promote Radioresistance in Breast Cancer
Authors: Ajeya Nandi, Rahul Debnath, Anupma Nayak, Tsun Ki Jerrick To, Gatha Thacker, Megan Reilly, Sanjeev Gumber, Ilias Karagounis, Ning Li, Christopher J. Lengner, Malay Haldar, Alana L. Welm, Andres M. Blanco, Christoforos Thomas, Rumela Chakrabarti
Journal: Cancer Research (2022)

Abstract Resistance to radiotherapy is a major obstacle for effective cancer treatment. Both cancer-associated fibroblasts (CAF) within the tumor microenvironment (TME) and Notch signaling are implicated in radioresistance, but their potential interrelationship is unclear. Here, we report that irradiated samples obtained from luminal breast cancer patient tumors express higher levels of the Notch ligand Dll1 and have a greater number of αSMA- and FAP-expressing activated CAFs. Single cell transcriptomic profiles further revealed enrichment of an αSMA+ myofibroblastic subpopulation of CAF in Dll1+ tumors. In murine and human patient-derived xenograft models, Dll1+ tumor cells were more radioresistant than Dll1– tumor cells, and genetic and pharmacologic blocking of Dll1-mediated Notch signaling decreased the number of Dll1+ cancer stem cells (CSC) and CAFs and increased Dll1+ tumor cell radiosensitivity. Dll1+ cells recruited CAFs in an IL6-dependent fashion and promoted Wnt ligand secretion by Notch2/3-expressing CAFs, thereby driving Wnt/β-catenin–dependent increases in Dll1+ CSC function to promote metastasis. Treatment with the porcupine inhibitor LGK-974 that inhibits Wnt ligand secretion or pharmacologic blockade of IL6 or Dll1 suppressed CAF-dependent enhancement of Dll1+ CSC function and metastasis in radioresistant tumors. Together, these findings reveal an essential cross-talk between Dll1+ cancer cells and CAFs, which promotes metastasis and radioresistance, which could be therapeutically exploited to improve the outcome of patients with breast cancer. Significance: Dll1+ breast cancer cells activate Notch signaling in cancer-associated fibroblasts that increases Wnt ligand secretion and leads to β-catenin–driven radioresistance and metastasis, opening new therapeutic avenues for breast cancer.
mRNA vaccines in the prevention and treatment of diseases
Authors: Yangzhuo Gu, Jiangyao Duan, Na Yang, Yuxin Yang, Xing Zhao
Journal: MedComm (2022)

Messenger ribonucleic acid (mRNA) vaccines made their successful public debut in the effort against the COVID-19 outbreak starting in late 2019, although the history of mRNA vaccines can be traced back decades. This review provides an overview to discuss the historical course and present situation of mRNA vaccine development in addition to some basic concepts that underly mRNA vaccines. We discuss the general preparation and manufacturing of mRNA vaccines and also discuss the scientific advances in the in vivo delivery system and evaluate popular approaches (i.e., lipid nanoparticle and protamine) in detail. Next, we highlight the clinical value of mRNA vaccines as potent candidates for therapeutic treatment and discuss clinical progress in the treatment of cancer and coronavirus disease 2019. Data suggest that mRNA vaccines, with several prominent advantages, have achieved encouraging results and increasing attention due to tremendous potential in disease management. Finally, we suggest some potential directions worthy of further investigation and optimization. In addition to basic research, studies that help to facilitate storage and transportation will be indispensable for practical applications.
Mycoplasma pneumoniae Pneumonia in an Urban Area
Authors: Hjordis M. Foy
Journal: JAMA (1970)

Incidence of Mycoplasma pneumoniae pneumonia was studied in a large medical cooperative in Seattle from 1963 through 1968. Twenty percent of all pneumonia was associated with M pneumoniae infection. The disease was endemic and without seasonal fluctuation during the last and the first two years of study. An epidemic started late in 1965 and peaked in January 1967. Children 5 to 9 years old consistently had the highest attack rate, while the proportion of all pneumonia due to M pneumoniae was highest among teenagers. Patients with M pneumoniae had higher rates of headache, fever, sore throat, skin rash, and ear complications, but lower rates of coryza and leukocytosis than patients with pneumonia of other etiologies. Duration of illness increased with age. Treatment with tetracyclines and erythromycin reduced the length of illness, but not the antibody response. Follow-up examinations revealed no serious sequelae.
Acute kidney injury in patients receiving pembrolizumab combination therapy versus pembrolizumab monotherapy for advanced lung cancer
Authors: Shruti Gupta, Ian A. Strohbehn, Qiyu Wang, Paul E. Hanna, Rituvanthikaa Seethapathy, Jason M. Prosek, Sandra M. Herrmann, Ala Abudayyeh, A. Bilal Malik, Sebastian Loew, Christopher A. Carlos, Wei-Ting Chang, Pazit Beckerman, Zain Mithani, Chintan V. Shah, Amanda D. Renaghan, Sophie de Seigneux, Luca Campedel, Abhijat Kitchlu, Daniel Sanghoon Shin, Gaia Coppock, Nuttha Lumlertgul, Pablo Garcia, David I. Ortiz-Melo, Arash Rashidi, Ben Sprangers, Vikram Aggarwal, Karolina Benesova, Kenar D. Jhaveri, Frank B. Cortazar, Astrid Weins, Yiqin Zuo, Meghan J. Mooradian, Kerry L. Reynolds, David E. Leaf, Meghan E. Sise, Luca Campedel, Joe-Elie Salem, Corinne Isnard Bagnis, Shruti Gupta, David E. Leaf, Harkarandeep Singh, Shveta S. Motwani, Naoka Murakami, Maria C. Tio, Suraj S. Mothi, Umut Selamet, Astrid Weins, Sebastian Loew, Kai M. Schmidt-Ott, Weiting Chang, Kenar D. Jhaveri, Rimda Wanchoo, Yuriy Khanin, Jamie S. Hirsch, Vipulbhai Sakhiya, Daniel Stalbow, Sylvia Wu, David I. Ortiz-Melo, Marlies Ostermann, Nuttha Lumlertgul, Nina Seylanova, Armando Cennamo, Anne Rigg, Nisha Shaunak, Zoe A. Kibbelaar, Karolina Benesova, Priya Deshpande, Meghan E. Sise, Kerry L. Reynolds, Harish S. Seethapathy, Meghan Lee, Ian A. Strohbhen, Meghan J. Mooradian, Paul E. Hanna, Qiyu Wang, Rituvanthikaa Seethapathy, Sandra M. Herrmann, Busra Isik, Ilya G. Glezerman, Frank B. Cortazar, Vikram Aggarwal, Sunandana Chandra, Jason M. Prosek, Sethu M. Madhavan, Dwight H. Owen, Marium Husain, Pazit Beckerman, Sharon Mini, Shuchi Anand, Pablo Garcia, Aydin Kaghazchi, Sunil Rangarajan, Daniel Sanghoon Shin, Grace Cherry, Christopher A. Carlos, Raymond K. Hsu, Andrey Kisel, Arash Rashidi, Sheru K. Kansal, Nicole Albert, Katherine Carter, Vicki Donley, Tricia Young, Heather Cigoi, Sophie De Seigneux, Thibaud Koessler, Ben Sprangers, Els Wauters, Chintan V. Shah, Mark Eijgelsheim, Zain Mithani, Javier A. Pagan, Yiqin Zuo, Gaia Coppock, Jonathan J. Hogan, Ala Abudayyeh, Omar Mamlouk, Jamie S. Lin, Valda Page, Abhijat Kitchlu, Samuel A.P. Short, Amanda D. Renaghan, Elizabeth M. Gaughan, A. Bilal Malik, Maria Jose Soler, Clara García-Carro, Sheila Bermejo, Enriqueta Felip, Eva Muñoz-Couselo, Maria Josep Carreras
Journal: Kidney International (2022)
Rituximab (Chimeric Anti-CD20 Monoclonal Antibody) Inhibits the Constitutive Nuclear Factor-κB Signaling Pathway in Non-Hodgkin's Lymphoma B-Cell Lines: Role in Sensitization to Chemotherapeutic Drug-induced Apoptosis
Authors: Ali R. Jazirehi, Sara Huerta-Yepez, Genhong Cheng, Benjamin Bonavida
Journal: Cancer Research (2005)

Abstract The chimeric anti-CD20 antibody rituximab (Rituxan, IDEC-C2B8) is widely used in the clinical treatment of patients with non-Hodgkin's lymphoma (NHL). Rituximab sensitizes NHL B-cell lines to drug-induced apoptosis via down-regulation of Bcl-xL expression. We hypothesized that the mechanism by which rituximab down-regulates Bcl-xL may be, in part, due to inhibition of constitutive nuclear factor-κB (NF-κB) activity that regulates Bcl-xL expression. This hypothesis was tested in CD20+ drug-resistant Ramos (Bcl-2−/Bcl-xL+) and Daudi (Bcl-2+/Bcl-xL+) cell lines. Rituximab decreased the phosphorylation of NF-κB-inducing kinase, IκB kinase, and IκB-α, diminished IKK kinase activity, and decreased NF-κB DNA binding activity. These events occurred with similar kinetics and were observed 3 to 6 hours post-rituximab treatment. Rituximab significantly up-regulated Raf-1 kinase inhibitor protein expression, thus interrupting the NF-κB signaling pathway concomitant with Bcl-xL and Bfl-1/A1 down-regulation. The role of NF-κB in the regulation of Bcl-xL transcription was shown using promoter reporter assays in which deletion of the two-tandem NF-κB binding sites in the upstream promoter region significantly reduced the luciferase activity. This was further corroborated by using IκB superrepressor cells and by NF-κB–specific inhibitors. The direct role of Bcl-xL in drug resistance was assessed by using Bcl-xL–overexpressing cells, which exhibited higher drug resistance that was partially reversed by rituximab. Rituximab-mediated inhibition of the NF-κB signaling pathway and chemosensitization was corroborated by the use of specific inhibitors. These findings reveal a novel pathway mediated by rituximab through Raf-1 kinase inhibitor protein induction that negatively regulates the constitutive NF-κB pathway and chemosensitization of the NHL B-cells.
Imipramine activates FAM3A-FOXA2-CPT2 pathway to ameliorate hepatic steatosis
Authors: Xiangyang Liu, Song Hou, Rui Xiang, Chengqing Hu, Zhenzhen Chen, Na Li, Han Yan, Xiaoxing Yu, Xin Li, Yujing Chi, Jichun Yang
Journal: Metabolism (2022)